Conduction Of Excitation Waves Research Articles

Conduction of excitation waves and reentry drift on cardiac tissue with simulated photocontrol-varied excitability.

The development of new approaches to suppressing cardiac arrhythmias requires a deep understanding of spiral wave dynamics. The study of spiral waves is possible in model systems, for example, in a monolayer of cardiomyocytes. A promising way to control cardiac excitability in vitro is the noninvasive photocontrol of cell excitability mediated by light-sensitive azobenzene derivatives, such as azobenzene trimethylammonium bromide (AzoTAB). The trans-isomer of AzoTAB suppresses spontaneous activity and excitation propagation speed, whereas the cis isomer has no detectable effect on the electrical properties of cardiomyocyte monolayers; cis isomerization occurs under the action of near ultraviolet (UV) light, and reverse isomerization occurs when exposed to blue light. Thus, AzoTAB makes it possible to create patterns of excitability in conductive tissue. Here, we investigate the effect of a simulated excitability gradient in cardiac cell culture on the behavior and termination of reentry waves. Experimental data indicate a displacement of the reentry wave, predominantly in the direction of lower excitability. However, both shifts in the direction of higher excitability and shift absence were also observed. To explain this effect, we reproduced these experiments in a computer model. Computer simulations showed that the explanation of the mechanism of observed drift to a lower excitability area requires not only a change in excitability coefficients (ion currents) but also a change in the diffusion coefficient; this may be the effect of the substance on intercellular connections. In addition, it was found that the drift direction depended on the observation time due to the meandering of the spiral wave. Thus, we experimentally proved the possibility of noninvasive photocontrol and termination of spiral waves with a mechanistic explanation in computer models.

Effects of fibroblast on electromechanical dynamics of human atrial tissue-insights from a 2D discrete element model.

Roughly 75% of normal myocardial tissue volume is comprised of myocytes, however, fibroblasts by number are the most predominant cells in cardiac tissue. Previous studies have shown distinctive differences in cellular electrophysiology and excitability between myocytes and fibroblasts. However, it is still unclear how the electrical coupling between the two and the increased population of fibroblasts affects the electromechanical dynamics of cardiac tissue. This paper focuses on investigating effects of fibroblast-myocyte electrical coupling (FMEC) and fibroblast population on atrial electrical conduction and mechanical contractility by using a two-dimensional Discrete Element Method (DEM) model of cardiac tissue that is different to finite element method (FEM). In the model, the electro-mechanics of atrial cells are modelled by a biophysically detailed model for atrial electrical action potentials and myofilament kinetics, and the atrial fibroblasts are modelled by an active model that considers four active membrane ionic channel currents. Our simulation results show that the FMEC impairs myocytes’ electrical action potential and mechanical contractibility, manifested by reduced upstroke velocity, amplitude and duration of action potentials, as well as cell length shortening. At the tissue level, the FMEC slows down the conduction of excitation waves, and reduces strain of the tissue produced during a contraction course. These findings provide new insights into understandings of how FMEC impairs cardiac electrical and mechanical dynamics of the heart.

Mechanistic Insights Into Inflammation-Induced Arrhythmias: A Simulation Study.

Cardiovascular diseases are the primary cause of death of humans, and among these, ventricular arrhythmias are the most common cause of death. There is plausible evidence implicating inflammation in the etiology of ventricular fibrillation (VF). In the case of systemic inflammation caused by an overactive immune response, the induced inflammatory cytokines directly affect the function of ion channels in cardiomyocytes, leading to a prolonged action potential duration (APD). However, the mechanistic links between inflammatory cytokine-induced molecular and cellular influences and inflammation-associated ventricular arrhythmias need to be elucidated. The present study aimed to determine the potential impact of systemic inflammation on ventricular electrophysiology by means of multiscale virtual heart models. The experimental data on the ionic current of three major cytokines [i.e., tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), and interleukin-6 (IL-6)] were incorporated into the cell model, and the effects of each cytokine and their combined effect on the cell action potential (AP) were evaluated. Moreover, the integral effect of these cytokines on the conduction of excitation waves was also investigated in a tissue model. The simulation results suggested that inflammatory cytokines significantly prolonged APD, enhanced the transmural and regional repolarization heterogeneities that predispose to arrhythmias, and reduced the adaptability of ventricular tissue to fast heart rates. In addition, simulated pseudo-ECGs showed a prolonged QT interval—a manifestation consistent with clinical observations. In summary, the present study provides new insights into ventricular arrhythmias associated with inflammation.

Pro-Arrhythmic Effects of Discontinuous Conduction at the Purkinje Fiber-Ventricle Junction Arising From Heart Failure-Induced Ionic Remodeling - Insights From Computational Modelling.

Heart failure is associated with electrical remodeling of the electrical properties and kinetics of the ion channels and transporters that are responsible for cardiac action potentials. However, it is still unclear whether heart failure-induced ionic remodeling can affect the conduction of excitation waves at the Purkinje fiber-ventricle junction contributing to pro-arrhythmic effects of heart failure, as the complexity of the heart impedes a detailed experimental analysis. The aim of this study was to employ computational models to investigate the pro-arrhythmic effects of heart failure-induced ionic remodeling on the cardiac action potentials and excitation wave conduction at the Purkinje fiber-ventricle junction. Single cell models of canine Purkinje fiber and ventricular myocytes were developed for control and heart failure. These single cell models were then incorporated into one-dimensional strand and three-dimensional wedge models to investigate the effects of heart failure-induced remodeling on propagation of action potentials in Purkinje fiber and ventricular tissue and at the Purkinje fiber-ventricle junction. This revealed that heart failure-induced ionic remodeling of Purkinje fiber and ventricular tissue reduced conduction safety and increased tissue vulnerability to the genesis of the unidirectional conduction block. This was marked at the Purkinje fiber-ventricle junction, forming a potential substrate for the genesis of conduction failure that led to re-entry. This study provides new insights into proarrhythmic consequences of heart failure-induced ionic remodeling.

Role of Oxidation-Dependent CaMKII Activation in the Genesis of Abnormal Action Potentials in Atrial Cardiomyocytes: A Simulation Study

Atrial fibrillation is a common cardiac arrhythmia with an increasing incidence rate. Particularly for the aging population, understanding the underlying mechanisms of atrial arrhythmia is important in designing clinical treatment. Recently, experiments have shown that atrial arrhythmia is associated with oxidative stress. In this study, an atrial cell model including oxidative-dependent Ca2+/calmodulin- (CaM-) dependent protein kinase II (CaMKII) activation was developed to explore the intrinsic mechanisms of atrial arrhythmia induced by oxidative stress. The simulation results showed that oxidative stress caused early afterdepolarizations (EADs) of action potentials by altering the dynamics of transmembrane currents and intracellular calcium cycling. Oxidative stress gradually elevated the concentration of calcium ions in the cytoplasm by enhancing the L-type Ca2+ current and sarcoplasmic reticulum (SR) calcium release. Owing to increased intracellular calcium concentration, the inward Na+/Ca2+ exchange current was elevated which slowed down the repolarization of the action potential. Thus, the action potential was prolonged and the L-type Ca2+ current was reactivated, resulting in the genesis of EAD. Furthermore, based on the atrial single-cell model, a two-dimensional (2D) ideal tissue model was developed to explore the effect of oxidative stress on the electrical excitation wave conduction in 2D tissue. Simulation results demonstrated that, under oxidative stress conditions, EAD hindered the conduction of electrical excitation and caused an unstable spiral wave, which could disrupt normal cardiac rhythm and cause atrial arrhythmia. This study showed the effects of excess reactive oxygen species on calcium cycling and action potential in atrial myocytes and provided insights regarding atrial arrhythmia induced by oxidative stress.

The role of the size of infarcted area on two kinds of vulnerable window in two dimension ventricular tissue.

Sudden cardiac death (SCD) is mainly induced by ventricular arrhythmia, especially among patients with myocardial infarction (MI). Previous studies have shown that ventricular tachycardia and fibrillation are thought to be caused by re-entrant waves of excitation. Although in heterogeneous tissue, the traditional vulnerable window of unidirectional block and the vulnerable window when bidirectional propagation was initiated could coexist, little studies are based on effects of infarcted areas on both vulnerable windows. The electrophysiology remodeling was based on TP06 model in the present study. In simulation of two-dimension (2D) ideal models, excitation wave conduction in ventricular tissue was simulated under three different types of stimulus. 2D ideal models of ventricular tissue were constructed as loop areas in the center of a square tissue with the resolution of 600×600 grid points and cell size of 0.35mm. Simulation results showed that the traditional vulnerable window when unidirectional propagation was initiated was consistent no matter where the position of stimulus is and how long and how wide the size of the infarcted area is. However, the vulnerable window when bidirectional propagation was initiated varies in different conditions. The traditional vulnerable window could not reflect the role of the infarcted area on arrhythmogenesis. The vulnerable window when bidirectional propagation was initiated increases with the increasement of the width and the length of the infarcted area with the appropriate position of the stimulus, which could help us to conclude the arrhythmogenesis according to the size of infarcted areas.

Slow [Na+]i dynamics impacts arrhythmogenesis and spiral wave reentry in cardiac myocyte ionic model.

Accumulation of intracellular Na+ is gaining recognition as an important regulator of cardiac myocyte electrophysiology. The intracellular Na+ concentration can be an important determinant of the cardiac action potential duration, can modulate the tissue-level conduction of excitation waves, and can alter vulnerability to arrhythmias. Mathematical models of cardiac electrophysiology often incorporate a dynamic intracellular Na+ concentration, which changes much more slowly than the remaining variables. We investigated the dependence of several arrhythmogenesis-related factors on [Na+]i in a mathematical model of the human atrial action potential. In cell simulations, we found that [Na+]i accumulation stabilizes the action potential duration to variations in several conductances and that the slow dynamics of [Na+]i impacts bifurcations to pro-arrhythmic afterdepolarizations, causing intermittency between different rhythms. In long-lasting tissue simulations of spiral wave reentry, [Na+]i becomes spatially heterogeneous with a decreased area around the spiral wave rotation center. This heterogeneous region forms a functional anchor, resulting in diminished meandering of the spiral wave. Our findings suggest that slow, physiological, rate-dependent variations in [Na+]i may play complex roles in cellular and tissue-level cardiac dynamics.

Comparison of Electric- and Magnetic-Cardiograms Produced by Myocardial Ischemia in Models of the Human Ventricle and Torso

Myocardial ventricular ischemia arises from a lack of blood supply to the heart, which may cause abnormal repolarization and excitation wave conduction patterns in the tissue, leading to cardiac arrhythmias and even sudden death. Current diagnosis of cardiac ischemia by the 12-lead electrocardiogram (ECG) has limitations as they are insensitive in many cases and may show unnoticeable differences to normal patterns. As the magnetic field provides extra information on cardiac excitation and is more sensitive to tangential currents to the surface of the chest, whereas the electric field is more sensitive to flux currents, it has been hypothesized that the magnetocardiogram (MCG) may provide a complementary method to the ECG in ischemic diagnosis. However, it is unclear yet about the differences in sensitivity regions of body surface ECG and MCG signals to ischemic conditions. The aim of this study was to investigate such differences by using 12-, 36- ECG and 36-MCG computed from multi-scale biophysically detailed computational models of the human ventricles and torso in both control and ischemic conditions. It was shown that ischemia produced changes in the ECG and MCG signals in the QRS complex, T-wave and ST-segment, with greater relative differences seen in the 36-lead ECG and MCG as compared to the 12-leads ECG (34% and 37% vs 26%, respectively). The 36-lead ECG showed more averaged sensitivity than the MCG in the change of T-wave due to ischemia (37% vs 32%, respectively), whereas the MCG showed greater sensitivity than the ECG in the change of the ST-segment (50% vs 40%, respectively). In addition, both MCG and ECG showed regional-dependent changes to ischemia, but with MCG showing a stronger correlation between ischemic region in the heart. In conclusion, MCG shows more sensitivity than ECG in response to ischemia, which may provide an alternative method for the diagnosis of ischemia.

Effect Of Verapamil On a Speed Of The Excitation Wave Conduction In The Isolated Rat Heart Myocardium

Event Abstract Back to Event Effect Of Verapamil On a Speed Of The Excitation Wave Conduction In The Isolated Rat Heart Myocardium Elena Kharkovskaia1*, Natalya Zhidkova2, Evgeniya Arkhipova3, Natalia Shchelchkova4, G. V. Osipov1 and Irina Mukhina1, 4 1 Lobachevsky State University, Russia 2 Lobachevsky State University, Russia 3 Nizhny Novgorod State Medical Academy, Russia 4 Nizhny Novgorod State Medical Academy, Russia Motivation Calcium antagonists are widely used in the treatment and prevention of heart diseases. Verapamil is a blocker of the slow L-type calcium channel. The action of verapamil in the heart accompanied by negative inotropic and chronotropic effects, since the restriction of entry of calcium ions leads to a quantifiable reduction in the formation of actin-myosin bonds in the working cardiomyocytes and to inhibition of spontaneous depolarization in the atypical cardiomyocytes of the conduction system. The concentration of calcium ions also affect the speed of propagation of a wave of electrical excitation due to the regulation of connexons, which is placed in the intercalated discs of cardiomyocytes. The aim of the study was to examine the effect of verapamil on the speed of propagation of the excitation wave in the ventricular myocardium of isolated rat heart with using FlexMEA72 (Multichannel Systems). Additionally, a comparison between speed values obtained under the influence of verapamil in normal conditions and under the influence of verapamil in the condition of hypoxia was carried out. Material and Methods Isolated hearts of outbred white rats were perfused by the Langendorff method. After 10 minutes of perfusion with Krebs-Henseleit solution (NaCl 118, KCl 4,7, CaCl2 2, MgSO4 1,2, KH2PO4 1,2, NaHCO3 20, glucose 10 mkmol/L) in an experimental group perfusion was held with addition of verapamil with a concentration of 7 mkmol / L. The condition of hypoxia was simulated by stopping delivery of carbogen to perfusion solution. The presence of hypoxia in the myocardium was verified by biochemical analysis evaluating the ratio of lactate/pyruvate. For registration of the electrical activity of the myocardium multi-electrode mapping setting with flexible matrices FlexMEA72 (Multichannel Systems) was used. The data were analyzed in the Cardio2D+ Software. Heart rate measured by the number of heart beats per minute. The speed of propagation of the wave excitation of the heart was calculated based on the difference between the values of time of occurrence of electrical potentials recorded by the electrodes of the matrix. Comparison of the average values of obtained parameters at different stages of the experiment, as well as a comparison of these values in the control and experimental groups, was performed by Student t-test for dependent samples. Differences were considered significant at a significance level of p <0.05. Results As a result of the study it was found that during the perfusion of the isolated rat heart with a solution containing verapamil heart rate decreased to 1.52 times compare with the control group. The velocity of propagation of excitation between the electrodes of the matrix was not changed. In hypoxic conditions with verapamil treatment velocity value increased to 1.8 times. Without verapamil hypoxia caused the velocity reducing to 1.4 times. Discussion The study was designed to investigate the effect of verapamil on the speed of propagation of electrical excitation in the myocardium under the normal conditions and under hypoxia and influence of verapamil simultaneously. To achieve this goal the Flexible microelectrode array «FlexMEA72» (Multichannel Systems) were used. Spatial and temporal resolution of arrays allowed to register the electrical excitation wave passing through the myocardium of the left ventricle and to evaluate its speed. The obtained results made it possible to estimate the effect of verapamil on the condition of cardiac tissue, based on the change in its conductivity during treatment with the drug. It was found that verapamil reduces heart rate, but the speed of excitation spreading in the myocardium remains unchanged. In case of hypoxia conductive velocity value decreased because of disruption of normal metabolism in cardiomyocytes. In the presence of verapamil effect of hypoxia expressed in increase of the speed of electrical wave propagation. Calcium influx leads to activation of myofibrillar adenosine triphosphatase which converts phosphate bound energy into mechanical work: thus calcium influx is an important determinant of myocardial oxygen consumption. Verapamil therefore, by limiting calcium influx, reduce calcium-dependent splitting of adenosine triphosphate, which in turn reduces myocardial oxygen demand and in this way can influence on the velocity by regulation of calcium concentration. Moreover, verapamil by helping to reduce energy consumption in the cells of the myocardium in some way produce increasing of conductive velocity, possibly by activating certain mechanisms aimed at restoring normal electrical conductivity. Conclusion Perfusion with a solution containing verapamil influenced on the calcium dynamics in myocardium of the isolated rat hearts that was expressed in a negative chronotropic effect. But this influence did not cause changes in the speed of propagation of the wave of excitation along the surface of the myocardium in normal conditions. It features the existence of specific mechanisms to prevent a change in the conductivity of the myocardium, causing the termination of calcium channels of L-type. But the presence of verapamil caused a negative chronotropic effect, indicating thereby suppression of sinus node activity. On the other hand, it was found that in the presence of verapamil in the perfusion solution hypoxia enhances electrical conductivity of the myocardium of the isolated heart. Thus, through the use of flexible multi-electrode arrays restoring effect of verapamil on the state of the myocardium during hypoxia was shown. Acknowledgements This research was supported by the Russian Science Foundation (Contract #14-12-00811). Keywords: Verapamil, L-type calcium channel, Isolated rat heart, excitation wave propagation, FlexMEA72, the conduction system Conference: MEA Meeting 2016 | 10th International Meeting on Substrate-Integrated Electrode Arrays, Reutlingen, Germany, 28 Jun - 1 Jul, 2016. Presentation Type: oral Topic: MEA Meeting 2016 Citation: Kharkovskaia E, Zhidkova N, Arkhipova E, Shchelchkova N, Osipov GV and Mukhina I (2016). Effect Of Verapamil On a Speed Of The Excitation Wave Conduction In The Isolated Rat Heart Myocardium. Front. Neurosci. Conference Abstract: MEA Meeting 2016 | 10th International Meeting on Substrate-Integrated Electrode Arrays. doi: 10.3389/conf.fnins.2016.93.00023 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Jun 2016; Published Online: 24 Jun 2016. * Correspondence: Dr. Elena Kharkovskaia, Lobachevsky State University, Nizhni Novgorod, Russia, elharkov@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Elena Kharkovskaia Natalya Zhidkova Evgeniya Arkhipova Natalia Shchelchkova G. V Osipov Irina Mukhina Google Elena Kharkovskaia Natalya Zhidkova Evgeniya Arkhipova Natalia Shchelchkova G. V Osipov Irina Mukhina Google Scholar Elena Kharkovskaia Natalya Zhidkova Evgeniya Arkhipova Natalia Shchelchkova G. V Osipov Irina Mukhina PubMed Elena Kharkovskaia Natalya Zhidkova Evgeniya Arkhipova Natalia Shchelchkova G. V Osipov Irina Mukhina Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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Modelling changes in transmural propagation and susceptibility to arrhythmia induced by volatile anaesthetics in ventricular tissue

Volatile anaesthetics such as halothane, isoflurane and sevoflurane inhibit membrane currents contributing to the ventricular action potential. Transmural variation in the extent of current blockade induces differential effects on action potential duration (APD) in the endocardium and epicardium which may be pro-arrhythmic. Biophysical modelling techniques were used to simulate the functional impact of anaesthetic-induced blockade of membrane currents on APD and effective refractory period (ERP) in rat endocardial and epicardial cell models. Additionally, the transmural conduction of excitation waves in 1-dimensional cell arrays, the tissue's vulnerability to arrhythmogenesis and dynamic behaviour of re-entrant excitation in 2-dimensional cell arrays were studied. Simulated anaesthetic exposure reduced APD and ERP in both epicardial and endocardial cell models. The reduction in APD was greater in endocardial than epicardial cells, reducing transmural APD dispersion consistent with experimental data. However, the transmural ERP dispersion was augmented. All three anaesthetics increased the width of the tissue's vulnerable window during which a premature stimulus could induce unidirectional conduction block but only halothane reduced the critical size of ventricular substrates necessary to initiate and sustain re-entrant excitation. All three anaesthetics accelerated the rate of re-entrant excitation waves, but only halothane prolonged the lifespan of re-entry. These data illustrate in silico, that modest changes in ion channel conductance abbreviate rat ventricular APD and ERP, reduce transmural APD dispersion, but augment transmural ERP dispersion. These changes collectively enhance the propensity for arrhythmia generation and provide a substrate for re-entry circuits with a longer half life than in control conditions.

Remodelling of cellular excitation (reaction) and intercellular coupling (diffusion) by chronic atrial fibrillation represented by a reaction-diffusion system

Human atrial tissue is an excitable system, in which myocytes are excitable elements, and cell-to-cell electrotonic interactions are via diffusive interactions of cell membrane potentials. We developed a family of excitable system models for human atrium at cellular, tissue and anatomical levels for both normal and chronic atrial fibrillation (AF) conditions. The effects of AF-induced remodelling of cell membrane ionic channels (reaction kinetics) and intercellular gap junctional coupling (diffusion) on atrial excitability, conduction of excitation waves and dynamics of re-entrant excitation waves are quantified. Both ionic channel and gap junctional coupling remodelling have rate dependent effects on atrial propagation. Membrane channel conductance remodelling allows the propagation of activity at higher rates than those sustained in normal tissue or in tissue with gap junctional remodelling alone. Membrane channel conductance remodelling is essential for the propagation of activity at rates higher than 300/min as seen in AF. Spatially heterogeneous gap junction coupling remodelling increased the risk of conduction block, an essential factor for the genesis of re-entry. In 2D and 3D anatomical models, the dynamical behaviours of re-entrant excitation waves are also altered by membrane channel modelling. This study provides insights to understand the pro-arrhythmic effects of AF-induced reaction and diffusion remodelling in atrial tissue.

Observations on electrical activity of the pregnant uterus, not in labor

1.1. Electrical activity associated with the uterus can be demonstrated in pregnancy prior to labor.2.2. In late pregnancy, from the thirty-fifth week onward, a high level of electrical activity is reached, signaling the approaching onset of labor.3.3. The very great variability and relative lack of pattern may suggest multiple foci and localized events, or sporadic pacemaker activity.4.4. Appearance of major diphasic slow waves probably indicates the conduction and spread of excitation waves.5.5. It appears that, toward the end of gestation, pacemaker activity, conduction of the excitation waves, and muscular response are activated in that order.6.6. From the thirty-fifth week onward, this epoch electrically speaking may have the physiologic function of preparation for the end of gestation by means of favoring activation of pacemaker, conduction, and response, and possibly the establishment of the hegemony of a single pacemaker.